Tetrahydro-1, 3, 5-thiadiazine-2-thiones



United States Patent 3,373,158 TETRAHYDRG-l,3,S-THIADIAZINE-Z-THlONESManfred Schorr, Frankfurt am Main, Walter Diirckheimer, Hattersheim amMain, and Georg Liirnmier, Frankfurt am Main, Germany, assiguors toFarbwerke Hoechst Aktiengesellschaft vormals Meister Lucius & Eruning,Frankfurt am Main, Germany, a

corporation of Germany No Drawing. Filed Feb. 19, 1965, Ser. No. 434,126Claims priority, application Germany, Feb. 20, 1964, F 42,061 10 Claims.(Cl. 260-243) ABSTRACT OF THE DISCLOSURETetrahydro-1,3,5-thiadiazine-2-thiones substituted in the 3-position bya halogen-substituted aralkyl and in the 5-position by lower alkyl,lower alkenyl or lower hydroxy alkyl. These compounds are goodfungistatics and bacteriostatics, and are especially useful for thetreatment of trematodes infections.

Various processes are already known for the preparation oftetrahydro-1,3,5-thiadiazine2-thiones by the reaction of primary amineswith hydrogen sulphide and an alkali metal and the subsequent reactionof formaldehyde and a further mol of a primary amine. In many cases thecompounds thus obtained have an inhibiting action, especially in thosecases where the tetrahydro-1,3,5-thiadiazine-Z-thione ring in 3-positionis substituted by a henzyl or phenylethyl radical, on the growth ofvarious microorganisms. This effect is especially marked towards fungi(cf. A. Rieche, G. Hilgetag. A. Martin, O. Nededly and J. Schlegel, ArchPharmaz., 293, 957 (1960)). Up to now it has, however, not yet beenknown whether the compounds mentioned above have an effect ontrematodes.

The present invention is based on the observation thattetrahydro-l,3,S-thiadiazine-Z-thiones of the formula wherein R is ahalogen-substituted aralkyl radical and R represents a lower alkyl,lower alkenyl or lower hydroxyalkyl radical, are obtained by convertinga primary amine of the general formula R NH wherein R has the meaninggiven above, in the presence of an alkali metal hydroxide or an alkalineearth metal hydroxide or carbonate, by the action of hydrogen sulphideinto the corresponding dithiocarbamic acid salt and then reactingthereon formaldehyde and the salt of an amine of the general formula R-NH wherein R has the meaning given above. The products thus obtainedare especially useful for the treatment of trematodes infections.

As halogen-aryl-alkyl-amines of the formula R -NH there are preferablyused benzyl or fi-phenylethyl-amines the benzene nucleus of which issubstituted by one or more halogen atoms. In addition, there may be usedcompounds having a long or a branched alkyl chain such as halogensubstituted phenylpropyl-amines or phenylbutylamines. In accordance withthe invention there may also be used as starting material an amine whosealkyl chain has several halogen-phenyl radicals. As suitable halogenatoms through which the benzene nuclei of the aralkylamines mentionedabove are substituted there come into consideration above all fluorine,chlorine and bromine, chlorine, however, being preferred. The followingamines may, for example, be used for the reaction:

3,373,158 Patented Mar. 12, 1968 4-chlorobenzylamine, 3,4-, 3,5- or2,5-dichlorobenzyl-amine, 4 bromobenzylamine, 4 fluorophenyl-ethylamine,3,4- or 2,4-dichlorophenyl-ethylamine, 4-chlorophenyl-propylamine,4-chlorophenyl-butylamine, 4-chloro a-ethylbenzylamine, 3,3 bis-(4chlorophenyl)-propylamine, 2,3-bis-(4-chlorophenyl)-propylamine,3,4-bis-(4- chlorophenyD-butylamiae,2,3-bis-(4-chlorophenyl)-pentylamine.

Further starting materials are the amines of the general formula R -NHwherein R represents an alkyl group having 1-6 carbon atoms, which groupmay also contain a double bond or may be substituted by one or severalhydroxyl groups. Among these substances the hydroxyalkylamines arepreferred. As examples there may be named the following compounds:methylamine, ethylamine, ethanolamine, isopropyl-amine, 3-aminopropanol,3-amino-l,2-propanediol, butylamine, 4-amino-butanol, allylamine,amylamine, hexylamine.

The process of the present invention is carried out as follows:

The corresponding dithiocarbamate is first prepared by reacting ahalogen-substituted aralkyl-amine with hydrogen sulphide and an alkalimetal. The reaction components may be used in molar portions. Thehydroxides or carbonates of alkali metals or alkaline earth metals maybe applied and sodium hydroxide or potassium hydroxide have been foundto be particularly useful. Advantageously, the process may be caried outas follows: Aralkylamine is first mixed with hydrogen sulphide in thepresence of a solvent, and an aqueous or alcoholic sodium hydroxidesolution is then added. As solvents there come into consideration: wateror polar organic solvents, for example, methanol, ethanol, acetone,dioxane, tetrahydrofurane or acetonitrile.

It is not necessary to isolate the salts of dithiocarbamic acid obtainedin the form of pure substances. Advantageously, they are at once furtherreacted in solution by adding at least 2 mols of formaldehyde,preferably in the form of an aqueous solution, and at least 1 mol of aneutral salt of an alkylamine or hydroxy-alkylamine. As acid componentsof the salt of the amine inorganic or organic acids may be used. Thesalts with hydrohalic acids, sulphuric acid, amido-sulphonic acid,phosphoric acid, acetic acid, propionic acid and others, for example,have been found useful. The hydrochlorides are advantageously applied.The reaction may be carried out at a slightly reduced or slightly raisedtemperature, the preferred method being to operate at room temperature.The salts of the amine are advantageously added in the dissolved stateto the reaction mixture. When all the components have been mixed, thetetrahydro-l,3,S-thiadiazine-Z-thiones, as a rule, rapidly precipitatefrom the reaction mixture. Sometimes, they are obtained in the form ofan oil. They crystallise after a short time or on rubbing with asuitable solvent and can then be isolated by filtration. In most casesthe products thus obtained are substantially pure and the yieldsgenerally amount to 100%. In some cases it may be advisable to carry outa further purification by recrystallisation. For this purpose ethylacetate is especially useful as a solvent. If for solubilitys sake it isnecessary to use an alcohol, there has to be operated as rapidly aspossible because tetrahydro-1,3,5-thiadiazine-2-thiones have thetendency to decompose on heating with water or organic solventscontaining hydroxyl groups, this causing a considerable reduction theyconstitute colourless crystalline powders which can be stored for anylength of time. Decomposition sets in only above the melting point.

The tetrahydro-1,3,S-thiadiazine-Z-thiones obtained by the process ofthe present invention may be used as medicaments. Just as the alreadyknown compounds of this of the yield. In the solid form I 3 4 class ofsubstances they are good fungistatics and bac- For combating parasitesthe products of the present teriostatics. invention are orallyadministered, either as such or in The following table illustrates theexcellent inhibiting the form of galenic preparations, for example,tablets, effect of some of the compounds of the present invention:capsules, dragees, juices or the like with admixture of TABLE [Bacteriostatic and tungistatic action of some of the1,3,5-tetrahydro-thiadiazine-2-thiones: (the concentrations given in-y/co. were sufiicient completely to inhibit the growth of the bacteriaand fungi enumerated)] Micro M zcro- T1icho- Tricho- Candida Staph.Strept. Enteroc. Proteus E. sparum sporum phytan phyio'n, albicans am.hemol. faecium vulgaris colt gypreum ca'mz's rubrum tonsumns 604 3-(4-chlorobenzyl) 5- (,B-hydroxy-ethyl) tetrahydro-1,3,5-thiadiazine-2-thione 1. 5 6 30 8 60 4 2 4 2 31 3- (3,4dich1or0benzyl)-5- (-y-hydroxypro tetrahydro-1,3,5thiadiaziue-2thione 0. 8 6. 62.5 31. 5 62. 5 4 2 2 l 16 3-(fi-4-ch1orophenylethyl)-5-n-butyl-tetrahydro-1,3,5-thiadiazi.ue2-thioue 0. 5 0. 5 0.5 0. 5 163-(B-4-ch1orophenylethyD-5(fi-hydroxyethyD-tetrahydro-l,3,5-thiadiazi.ue-2-thione 2 7. 8 62. 5 7. 8 12. 50 2 4 2 2 313-(B-3,4-dich10rophenylethyl)-5-(fl-hydroxyethyl)-tetrahydro1,3,5-thiadiazine-2- thione 7.3 3.5 12.5

In addition, the products obtained by the process of -3pharmacologically tolerable carriers such as talc, starch, the presentinvention show a strong anthelmintic action lactose, tragacanth,magnesium stearate and others. The particularly on the various kinds ofleeches. Especially quantity per unit to be administered preferablyamounts striking is their action on Opisthorchis felineus. A conto50-500 mg. siderable importance must be attributed to the infestment Forcombating bacteria and fungi the products may be of domestic animals inmany countries all over the earth -35 administered in the form of ajelly, powder, ointment, with liver fluke. Efiicacious medicaments forcombating paste, shaking mixture, tincture, solution or suspensionFasciola hepatica and Dicrocolium dendriticum are alwith admixture ofpharmacologically tolerable carriers. ready known and administered on alarge scale in veterin- The active substances may be added to thegalenic prepary practice, whereas up to now there does not exist anyarations in a concentration of 0.5 to 10%, preferably specificallyactive chemo-therapeutic preparation for 2to 3%. combating the variouskinds of Opisthorchis (Opisthorcht's The following examples illustratethe invention: felineus, Opisthorchis viveroini, Opisthorchis sincnsis).

The chemo-therapeutic investigations were carried out EXAMPLEI forexperimental purposes on golden hamsters infected l y y)-5-(/3-hydr0xy-ethyl)-tetrahydrowith Opisthorchis felineus. The testedcompounds were 1,3,5-thiadiazine-2-thione orally administered to theanimals on the whole thrice on consecutive days. The success of thetreatment was ascertained by examination of the faeces with the aid ofthe Telemann-process prior to the treatment and :by two furtherexaminations on the fourteenth and twentieth day after the treatment andby a post-mortem examination of the animals. As dosis curativa minimawas regarded the dose after the third administration of which theinfestment with Opisthorchis felineus had been overcome. The followingtable illustrates the values found in the golden hamster test withregard to some of the products obtained by the process of the presentinvention. Moreover, some compounds described in Arch. Pharm., 293, 957(1960) and comparable With the products of the present invention asregards their structure are enumerated; said com- 31.1 grams of4-chlorophenylethylamine are dissolved in 100 cc. of acetonitrile, and12.1 cc. of hydrogen sulphide and 0.2 mol of sodium hydroxide solutionof 10% strength are dropwise added to the solution at 20 C., whilestirring. V

A solution of sodium-4-chlorophenylethyl-dithiocarbamate is obtained towhich, after 30 minutes, first 30 cc. of formaldehyde solution of 40%strength and then 12.1 grams of ethanolamine in 100 cc. of 2N-hydrochloric acid are added. The3-(4-chlorophenylethyl)-5-(fi-hydroxy-ethyl)-tetrahydro-1,3,5thiadiazine 2 thione immediately precipitates in the form of an oil andcrystallises on rubbing. It can be recrystallised from ethyl acetate/petroleum ether. It melts at 88-89 C.

pounds, however, do not show any action on Opisthorchis 5O EXAMPLE 2felirzeus. The introduction of halogen into the aralkyl 3-(4.fl rphenylethyl)-5-(B-hydr0xy-erh l) radical thus causes, and this beingsurprising, an entirely hy 1, 3, one

new biological effect. This could hardly be expected because among thewater-soluble 3-aralkyl-tetrahydro-1,3,5- grams of4'fi11Y0Ph6I1y1thy1aII11H6 are dlSSOlVfid 1 thiadiazine44hiones, as theyare described by A Rieche, 100 cc. of acetonitrile, and 12.1 cc ofhydrogen sulphide D Martin and Schade in Arch Phal-m 296, 770 and 0.2mol of sodium hydroxide solution of 10% (1963), the fungistaticefficiency of the compounds com strength are dropwise added to thesolution at 20 C., siderably decreases by the introduction ofsubstituents Whlla Snmng- After 30 there are added firstso into thearomatic ring. cc. of formaldehyde solution of 40% strength and thenTABLE 12.2 grams of ethanolamine in 100 cc. of 2 N-hydrochloric acid. Anoil precipitates which rapidly crystallises. By gf g g recrystallisationfrom ethyl acetate the 3-(4-fluorophenyl- Substance mg./ kg. of bodyethyl) 5 (B-hydroxyethyl) tetrahydro 1,3,5 thia- Welght pewsdiazine-2-thione'may be purified. The product melts at3-(4-chltgtzlfienzyl)-5-n-butyl-tetrahydro-l,3,5-thiadi- 3X 200 97-99 C.

fiZlIle- 1 no. 3-(l li-f(liuorfghgeiiglehyl)-5-figydr0xy-ethyl)-tetra-3X 100 EXAMPLE 3 I 7 I lZlIle- 10718. 3-gi fid iciilaogogfi yl):5-(-lgdroxy-propyl)-tetra- 3X m0 -[vo- 1 r )-p py I y n- ,,1 1n-1u. att g f lg fi g g f s g gg a; 5 2 ggv BX 200 ethyl) tetlahydm 1,3,5thmdlazme 2 throne I 1 11 S-lignZyI-igggigdi xy-ethyl3 t1 a li;dro-1?3,Ethiadi- (I) grams of 'Y/Y- P Y )-P Py are a lamedissolved in200 cc. of acetonitrile and 12.1 cc. of hydro- 3- 1- A 14; t n -1,3,5-thd -2- v t id? Drew 8 r8 ydro 12 1 gen sulphide and 0.2 mol of sodiumhydroxide solution of si h e lg lm -sase ro yl-hetmhydro-l,3,5 th ad a(l) 10% strength are dropwise added to the solution at 20 C., whilestirring. After 30 minutes there are first added 30 cc. of formaldehydesolution of 40% strength and then 12.2 grams of ethanolamine in 100 cc.of 2N- hydrocholoric acid. The 3-['y,'y-biS-(4-chl0r0phenyl) propyl] 5(fi-hydroxy-ethyl) tetrahydro 1,3,5 thiadiazine-Z-thione precipitates inthe form of an oil which partially crystallises after standing forseveral days. There is digested with ether and the colourless crystalsare filtered with suction. They can be purified by recrystallisationfrom ethyl acetate. The product melts at 128-129 C.

EXAMPLE 4 3-(3,4-dicl1l0robenzyl)5-(y-hydr0xy-propyl)tetrahydro-1,3,5-thiadiazin e-Z-th ione 35.2 grams of3,4-dichlorobenzylamine are dissolved in 100 cc. of acetonitrile, and12.1 cc. of hydrogen sulphide and 0.2 mol of a sodium hydroxide solutionof 10% strength are dropwise added to the solution at 20 C., whilestirring. After 30 minutes there are first added 30 cc. of formaldehydesolution of 40% strength and then 15 grams of 3-aminopropanol in 100 cc.of 2 N-hydrochloric acid. The oil which precipitates is dissolved inethyl acetate, dried and filtered through a short column of aluminiumoxide. On cooling to 20 C. the 3-(3,4- dichlorobenzyl) 5('y-hydroxypropyl) tetrahydro- 1,3,S-thiadiazine-Z-thione separates inthe form of colourless crystals which melt at 118 C.

EXAMPLE 5 3- (4-fluorobenzyl) -5- ('y-hydroxy-propyl) -tetrahydr1,3,5-thz'adiazine-2thione 25 grams of 4-fluorobenzylamine are dissolvedin 100 cc. of acetonitrile, and 12.1 cc. of hydrogen sulphide and 0.2mol of sodium hydroxide solution of 10% strength are dropwise added tothe solution at 20 C., while stirring. After 30 minutes there are addedfirst 30 cc. of formaldehyde solution of 40 percent strength and then 15grams of 3-amino-propanol in 100 cc. of 2 N-hydrochloric acid. The oilwhich precipitates solidifies on cooling and rubbing. Byrecrystallisation from ethyl acetate the 3-(4- fiuorobenzyl)(v-hydroxy-propyl) tetrahydro 1,3, S-thiadiazine-Z-thione can be furtherpurified. The product melts at 121 C.

EXAMPLE 6 3- (3,4-dz'ch lorophenylethyl) -5-(;8-hydroxy-ethyl)tetrahydr0-1,3,5-thiadiazine-Z-thione 38 grams of3,4-dichlorophenylethyl-amine are dissolved in 100 cc. of acetonitrile,and 12.1 cc. of hydrogen sulphide, and 0.2 mol of sodium hydroxidesolution of strength are dropwise added at 20 C., While stirring. After30 minutes there are added first 30 cc. of formaldehyde solution of 40%strength and then 12.2 grams of ethanolamine in 100 cc. of 2N-hydrochloric acid. The3-3(3,4-dichlorophenylethyl)-5-(,B-hydroxyethyl)tetrahydro-l,3,5-thiadiazine-2-thioneprecipitates in the form of an oil which crystallises on rubbing. It canbe further purified by recrystallisation from ethyl acetate. The productmelts at 125-126 C.

EXAMPLE 7 3- (4-chlor0ber1zyl) 5-n-butyl-tetrahydro-1,3,5-thiadiazine-Z-thione 28.3 grams of 4-chlorobenzyl-amine are dissolved in100 cc. of acetonitrile, and 12.1 cc. of hydrogen sulphide and 0.2 molof sodium hydroxide solution of 10% strength are dropwise added at 20 C.while stirring. To the solution of sodium-4-chlorophenyl-dithiocarbamatethus formed there are added after 30 minutes first 30 cc. offormaldehyde solution of 40% strength and then 14.6 grams ofn-butylamine in 100 cc. of 2 N-hydrochloric acid. An oil precipitateswhich crystallises on cooling and rubbing. The3-(4-chlorobenzyl)5-n-butyl-tetrahydro-1, 3,5-thiadiazine-2-thione canbe further purified by recrystallisation from ethyl acetate. The productmelts at 110-111" C.

6 EXAMPLE 8 3- (4-ch lorobenzyl) 5- (fl-hydroxy-ethyl tetrahydro- 1 ,3,5 lhiad z'azine-Z-thione 4-chlorobenzyl-dithiocarbamate is prepared bythe process described in Example 7. To the solution there are addedfirst 30 cc. of formaldehyde solution of 40% strength and then 12.2grams of ethanolamine in cc. of ZN-hydrochloric acid, during whichoperation the reaction product precipitates in the form of an oil. The 3(4 chlorobenzyl) 5 (t3 hydroXy ethyl) tetrahydro 1,3,5 thiadiazine 2thione crystallises on cooling and rubbing. It can be further purifiedby recrystallisation from ethyl acetate. The product melts at 93-94" C.

EXAMPLE 9 3- (4-ch lorophenylethyl) 5-n-hexyl-tetrahydr0-],3,5-lhiadiazine-Z-thione 4-chlrophenylethyldithiocarbarnate is prepared bythe process described in Example 1. To the solution thus obtained thereare added first 30 cc. of formaldehyde solution of 40% strength and then20.2 grams of n-hexylamine in 100 cc. of 2 N-hydrochloric acid. The oilwhich precipitates is separated by decanting. On rubbing with methanolcrystals of3-(4-chlorophenylethyl)5-n-hexyltetrahydro-1,3,S-thiadiazine-Z-thioneare obtained. They are dissolved and allowed to crystallise first frommethanol and then from ether, While low cooling. The product melts at 72C.

EXAMPLE 10 3-(4-chl0rophenylezhyl) 5-methyl-tetrahydr0-],3,5thiadiazine-Z-thione A solution ofsodium4-chlorophenylethyl-dithiocarbamate is prepared by the processdescribed in Example 1. There are added thereto first 30 cc. offormaldehyde solution of 40% strength and then 6.2 grams of ethylaminein 100 cc. of 2 N-hydrochloric acid, during which operation the 3 (4chlorophenylethyl)5-methyl-tetrahydro-1,3,5- thiadiazine-Z-thioneprecipitates in the form of an oil and crystallises rapidly. Ifnecessary, the product is purified by recrystallising it fromethylacetate. It melts at 123 C.

EXAMPLE 1 1 3- (4-ch loropheny lethyl) 5-allyl-tetrahydr0-],3,5 tiliadiazine-2th ione 4-chlorophenylethyldithiocarbamate is prepared asdescribed in Example 1. There are added to the solution first 30 cc. offormaldehyde-solution of 40% strength and then 11.4 grams of allylaminein 100 cc. of 2 N-hydrochloric acid, during which operation the3-(4-chlorophenyl'ethyl) 5 allyl tetrahydro-1,3,5-thiadiazine-2- thioneprecipitates in the form of an oil and crystallises on cooling andrubbing. The product may be further purified by recrystallisation fromethyl acetate. It melts at 143 C.

EXAMPLE 12 3-(4-chl0r0phenylethyl)-5-i-buzyl-tetrahydr0-1,3,5-thiadiazine-Z-Ihione The sodium 4-chlorophenylethyl-dithiocarbamate isobtained by the process described in Example 1. To the solution of thesalt obtained there are added first 30 cc. of formaldehyde solution of40% strength and then 14.6 grams of i-butylamine in 100 cc. of 2N-hydrochloric acid. The 3-(4-chlorophenylethyl)-5-i-butyltetrahydro-1,3,S-thiadiazine-Z-thione precipitates in the form of an oil andcrystallises on cooling and rubbing. The product can be further purifiedby recrystallisation from ethyl acetate. It melts at 84-85 C.

EXAMPLE 13 3- (2,4-dichl0r0phenylelhyl) 5- (fi-hydroxy-erhyl)tetra/1ydro-I,iS-Ihiadiazine-Z-th ione 38 grams of2,4-dichlorophenylethylamine are dissolved in 100 cc. of acetonitrile,and 12.1 cc. of hydrogen sulphide and 0.2 mol of sodium hydroxidesolution of strength are dropwise added to the solution at C, whilestirring. After minutes there are added to the solution of the2,4-dichlorophenylethyl-dithiocarbamate =formed first 30 cc. offormaldehyde solution of strength and then 12,2 g. of ethanolamine incc. of 2 N-hydrochloride acid. The oil which precipitates solidifies oncooling and rubbing. The 3-(2,4-dichl0rophenylethyl) 5 (B hydroxyethyl)-tetrahydr0-l,3,5- thiadiazine-Z-thione can be further purified byrecrystallisa'tion from ethyl acetate. It melts at 137 C.

We claim:

1. A compound of he formula t l RLN N-R 10. 3(2,4-dichlorophenylethyl)-5-(/3-hydroXy-ethyl)-tetrahydro-1,3,5-thiadiazine-2-thione.

References Cited UNITED STATES PATENTS 2,838,389 6/1958 Yoder 260-2433,085,046 4/1963 Cummins 260-243 FOREIGN PATENTS 232,707 2/ 1959Australia. 1,149,014 2/1964. Germany.

OTHER REFERENCES Rieche et al.: Archiv Pharmazie, vol. 293, pp. 957-67Shah et al., J. Indian Chem. Soc., vol. 41, pp. 225-7 (1964).

NORMA S. MILESTONE, Acting Primary Examiner.

I. M. FORD, Assistant Examiner.

